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. 1995 Oct;69(10):6466–6472. doi: 10.1128/jvi.69.10.6466-6472.1995

Vesicular stomatitis virus infection of the central nervous system activates both innate and acquired immunity.

Z Bi 1, M Barna 1, T Komatsu 1, C S Reiss 1
PMCID: PMC189547  PMID: 7545248

Abstract

Vesicular stomatitis virus (VSV) causes acute infection of the central nervous system (CNS) when intranasally applied. We have examined cellular inflammatory changes in the CNS following VSV infection. As early as 1 day postinfection (p.i.), astrocytes were activated in the olfactory bulb (OB). This was followed by activation of microglia, first observed in the OB at day 3 p.i. Expression of inducible nitric oxide synthase was observed in activated microglia in the OB at day 3 p.i., and increased inducible nitric oxide synthase expression coincided with decreased virus titers in tissue homogenates. Expression of major histocompatibility complex (MHC) class I molecules on astrocytes and microglial, endothelial, and ependymal cells was also rapidly induced and followed by induced expression of MHC class II molecules on astrocytes and microglial and endothelial cells. Consistent with the pattern of viral dissemination, MHC molecules were expressed temporally from the rostral-to-caudal direction. Infiltration of CD8+ cells was observed as early as 1 day p.i. in the OB. CD4+ cells were detected in the OB at day 4 p.i. Increasing T-cell infiltration coincided with decreased virus titers. In contrast, B-cell infiltration of the CNS was not detected until day 14 p.i., after the virus was cleared and mice were showing behavioral signs of recovery. Breakdown of the blood-brain barrier was detected beginning at day 6 p.i., was most severe at day 8 p.i., and was followed by full recovery. Collectively, these data show that both innate immunity (production of nitric oxide) and acquired immunity (expression of MHC molecules and T-cell infiltration) are activated following VSV infection in the CNS.

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Selected References

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  1. Albelda S. M., Smith C. W., Ward P. A. Adhesion molecules and inflammatory injury. FASEB J. 1994 May;8(8):504–512. [PubMed] [Google Scholar]
  2. Bi Z., Reiss C. S. Inhibition of vesicular stomatitis virus infection by nitric oxide. J Virol. 1995 Apr;69(4):2208–2213. doi: 10.1128/jvi.69.4.2208-2213.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bredt D. S., Snyder S. H. Nitric oxide: a physiologic messenger molecule. Annu Rev Biochem. 1994;63:175–195. doi: 10.1146/annurev.bi.63.070194.001135. [DOI] [PubMed] [Google Scholar]
  4. Böhme G. A., Bon C., Stutzmann J. M., Doble A., Blanchard J. C. Possible involvement of nitric oxide in long-term potentiation. Eur J Pharmacol. 1991 Jul 9;199(3):379–381. doi: 10.1016/0014-2999(91)90505-k. [DOI] [PubMed] [Google Scholar]
  5. Chaturvedi U. C., Dhawan R., Khanna M., Mathur A. Breakdown of the blood-brain barrier during dengue virus infection of mice. J Gen Virol. 1991 Apr;72(Pt 4):859–866. doi: 10.1099/0022-1317-72-4-859. [DOI] [PubMed] [Google Scholar]
  6. Corradin S. B., Mauël J., Donini S. D., Quattrocchi E., Ricciardi-Castagnoli P. Inducible nitric oxide synthase activity of cloned murine microglial cells. Glia. 1993 Mar;7(3):255–262. doi: 10.1002/glia.440070309. [DOI] [PubMed] [Google Scholar]
  7. Cserr H. F., Knopf P. M. Cervical lymphatics, the blood-brain barrier and the immunoreactivity of the brain: a new view. Immunol Today. 1992 Dec;13(12):507–512. doi: 10.1016/0167-5699(92)90027-5. [DOI] [PubMed] [Google Scholar]
  8. Dhib-Jalbut S. S., Cowan E. P. Direct evidence that interferon-beta mediates enhanced HLA-class I expression in measles virus-infected cells. J Immunol. 1993 Dec 1;151(11):6248–6258. [PubMed] [Google Scholar]
  9. Fabry Z., Raine C. S., Hart M. N. Nervous tissue as an immune compartment: the dialect of the immune response in the CNS. Immunol Today. 1994 May;15(5):218–224. doi: 10.1016/0167-5699(94)90247-X. [DOI] [PubMed] [Google Scholar]
  10. Farrar M. A., Schreiber R. D. The molecular cell biology of interferon-gamma and its receptor. Annu Rev Immunol. 1993;11:571–611. doi: 10.1146/annurev.iy.11.040193.003035. [DOI] [PubMed] [Google Scholar]
  11. Fontana A., Fierz W., Wekerle H. Astrocytes present myelin basic protein to encephalitogenic T-cell lines. Nature. 1984 Jan 19;307(5948):273–276. doi: 10.1038/307273a0. [DOI] [PubMed] [Google Scholar]
  12. Forger J. M., 3rd, Bronson R. T., Huang A. S., Reiss C. S. Murine infection by vesicular stomatitis virus: initial characterization of the H-2d system. J Virol. 1991 Sep;65(9):4950–4958. doi: 10.1128/jvi.65.9.4950-4958.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Galea E., Reis D. J., Feinstein D. L. Cloning and expression of inducible nitric oxide synthase from rat astrocytes. J Neurosci Res. 1994 Feb 15;37(3):406–414. doi: 10.1002/jnr.490370313. [DOI] [PubMed] [Google Scholar]
  14. Gombold J. L., Weiss S. R. Mouse hepatitis virus A59 increases steady-state levels of MHC mRNAs in primary glial cell cultures and in the murine central nervous system. Microb Pathog. 1992 Dec;13(6):493–505. doi: 10.1016/0882-4010(92)90015-G. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Harris N., Buller R. M., Karupiah G. Gamma interferon-induced, nitric oxide-mediated inhibition of vaccinia virus replication. J Virol. 1995 Feb;69(2):910–915. doi: 10.1128/jvi.69.2.910-915.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hertz L., McFarlin D. E., Waksman B. H. Astrocytes: auxiliary cells for immune responses in the central nervous system? Immunol Today. 1990 Aug;11(8):265–268. doi: 10.1016/0167-5699(90)90106-j. [DOI] [PubMed] [Google Scholar]
  17. Huang A. S., Manders E. K. Ribonucleic acid synthesis of vesicular stomatitis virus. IV. Transcription by standard virus in the presence of defective interfering particles. J Virol. 1972 Jun;9(6):909–916. doi: 10.1128/jvi.9.6.909-916.1972. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Huneycutt B. S., Bi Z., Aoki C. J., Reiss C. S. Central neuropathogenesis of vesicular stomatitis virus infection of immunodeficient mice. J Virol. 1993 Nov;67(11):6698–6706. doi: 10.1128/jvi.67.11.6698-6706.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Huneycutt B. S., Plakhov I. V., Shusterman Z., Bartido S. M., Huang A., Reiss C. S., Aoki C. Distribution of vesicular stomatitis virus proteins in the brains of BALB/c mice following intranasal inoculation: an immunohistochemical analysis. Brain Res. 1994 Jan 28;635(1-2):81–95. doi: 10.1016/0006-8993(94)91426-5. [DOI] [PubMed] [Google Scholar]
  20. Joly E., Oldstone M. B. Neuronal cells are deficient in loading peptides onto MHC class I molecules. Neuron. 1992 Jun;8(6):1185–1190. doi: 10.1016/0896-6273(92)90138-4. [DOI] [PubMed] [Google Scholar]
  21. Karupiah G., Xie Q. W., Buller R. M., Nathan C., Duarte C., MacMicking J. D. Inhibition of viral replication by interferon-gamma-induced nitric oxide synthase. Science. 1993 Sep 10;261(5127):1445–1448. doi: 10.1126/science.7690156. [DOI] [PubMed] [Google Scholar]
  22. Kündig T. M., Hengartner H., Zinkernagel R. M. T cell-dependent IFN-gamma exerts an antiviral effect in the central nervous system but not in peripheral solid organs. J Immunol. 1993 Mar 15;150(6):2316–2321. [PubMed] [Google Scholar]
  23. Lee S. C., Dickson D. W., Brosnan C. F., Casadevall A. Human astrocytes inhibit Cryptococcus neoformans growth by a nitric oxide-mediated mechanism. J Exp Med. 1994 Jul 1;180(1):365–369. doi: 10.1084/jem.180.1.365. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Levine B., Hardwick J. M., Trapp B. D., Crawford T. O., Bollinger R. C., Griffin D. E. Antibody-mediated clearance of alphavirus infection from neurons. Science. 1991 Nov 8;254(5033):856–860. doi: 10.1126/science.1658936. [DOI] [PubMed] [Google Scholar]
  25. Lotan M., Schwartz M. Cross talk between the immune system and the nervous system in response to injury: implications for regeneration. FASEB J. 1994 Oct;8(13):1026–1033. doi: 10.1096/fasebj.8.13.7926367. [DOI] [PubMed] [Google Scholar]
  26. Lundh B., Kristensson K., Norrby E. Selective infections of olfactory and respiratory epithelium by vesicular stomatitis and Sendai viruses. Neuropathol Appl Neurobiol. 1987 Mar-Apr;13(2):111–122. doi: 10.1111/j.1365-2990.1987.tb00175.x. [DOI] [PubMed] [Google Scholar]
  27. Mucke L., Eddleston M. Astrocytes in infectious and immune-mediated diseases of the central nervous system. FASEB J. 1993 Oct;7(13):1226–1232. doi: 10.1096/fasebj.7.13.8405808. [DOI] [PubMed] [Google Scholar]
  28. Müller U., Steinhoff U., Reis L. F., Hemmi S., Pavlovic J., Zinkernagel R. M., Aguet M. Functional role of type I and type II interferons in antiviral defense. Science. 1994 Jun 24;264(5167):1918–1921. doi: 10.1126/science.8009221. [DOI] [PubMed] [Google Scholar]
  29. Nathan C., Xie Q. W. Nitric oxide synthases: roles, tolls, and controls. Cell. 1994 Sep 23;78(6):915–918. doi: 10.1016/0092-8674(94)90266-6. [DOI] [PubMed] [Google Scholar]
  30. Palmer R. M., Ferrige A. G., Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature. 1987 Jun 11;327(6122):524–526. doi: 10.1038/327524a0. [DOI] [PubMed] [Google Scholar]
  31. Pearce B. D., Hobbs M. V., McGraw T. S., Buchmeier M. J. Cytokine induction during T-cell-mediated clearance of mouse hepatitis virus from neurons in vivo. J Virol. 1994 Sep;68(9):5483–5495. doi: 10.1128/jvi.68.9.5483-5495.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Plakhov I. V., Arlund E. E., Aoki C., Reiss C. S. The earliest events in vesicular stomatitis virus infection of the murine olfactory neuroepithelium and entry of the central nervous system. Virology. 1995 May 10;209(1):257–262. doi: 10.1006/viro.1995.1252. [DOI] [PubMed] [Google Scholar]
  33. Ransohoff R. M., Hamilton T. A., Tani M., Stoler M. H., Shick H. E., Major J. A., Estes M. L., Thomas D. M., Tuohy V. K. Astrocyte expression of mRNA encoding cytokines IP-10 and JE/MCP-1 in experimental autoimmune encephalomyelitis. FASEB J. 1993 Apr 1;7(6):592–600. doi: 10.1096/fasebj.7.6.8472896. [DOI] [PubMed] [Google Scholar]
  34. Seguin M. C., Klotz F. W., Schneider I., Weir J. P., Goodbary M., Slayter M., Raney J. J., Aniagolu J. U., Green S. J. Induction of nitric oxide synthase protects against malaria in mice exposed to irradiated Plasmodium berghei infected mosquitoes: involvement of interferon gamma and CD8+ T cells. J Exp Med. 1994 Jul 1;180(1):353–358. doi: 10.1084/jem.180.1.353. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Snyder S. H. Nitric oxide: first in a new class of neurotransmitters. Science. 1992 Jul 24;257(5069):494–496. doi: 10.1126/science.1353273. [DOI] [PubMed] [Google Scholar]
  36. Steinhoff U., Müller U., Schertler A., Hengartner H., Aguet M., Zinkernagel R. M. Antiviral protection by vesicular stomatitis virus-specific antibodies in alpha/beta interferon receptor-deficient mice. J Virol. 1995 Apr;69(4):2153–2158. doi: 10.1128/jvi.69.4.2153-2158.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Stenger S., Thüring H., Röllinghoff M., Bogdan C. Tissue expression of inducible nitric oxide synthase is closely associated with resistance to Leishmania major. J Exp Med. 1994 Sep 1;180(3):783–793. doi: 10.1084/jem.180.3.783. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Tanaka Y., Adams D. H., Shaw S. Proteoglycans on endothelial cells present adhesion-inducing cytokines to leukocytes. Immunol Today. 1993 Mar;14(3):111–115. doi: 10.1016/0167-5699(93)90209-4. [DOI] [PubMed] [Google Scholar]
  39. Taub D. D., Lloyd A. R., Conlon K., Wang J. M., Ortaldo J. R., Harada A., Matsushima K., Kelvin D. J., Oppenheim J. J. Recombinant human interferon-inducible protein 10 is a chemoattractant for human monocytes and T lymphocytes and promotes T cell adhesion to endothelial cells. J Exp Med. 1993 Jun 1;177(6):1809–1814. doi: 10.1084/jem.177.6.1809. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Vanguri P., Farber J. M. IFN and virus-inducible expression of an immediate early gene, crg-2/IP-10, and a delayed gene, I-A alpha in astrocytes and microglia. J Immunol. 1994 Feb 1;152(3):1411–1418. [PubMed] [Google Scholar]
  41. Wang Y. F., Calder V. L., Greenwood J., Lightman S. L. Lymphocyte adhesion to cultured endothelial cells of the blood-retinal barrier. J Neuroimmunol. 1993 Nov-Dec;48(2):161–168. doi: 10.1016/0165-5728(93)90188-5. [DOI] [PubMed] [Google Scholar]
  42. Weinstein D. L., Walker D. G., Akiyama H., McGeer P. L. Herpes simplex virus type I infection of the CNS induces major histocompatibility complex antigen expression on rat microglia. J Neurosci Res. 1990 May;26(1):55–65. doi: 10.1002/jnr.490260107. [DOI] [PubMed] [Google Scholar]
  43. Welsh R. M., Brubaker J. O., Vargas-Cortes M., O'Donnell C. L. Natural killer (NK) cell response to virus infections in mice with severe combined immunodeficiency. The stimulation of NK cells and the NK cell-dependent control of virus infections occur independently of T and B cell function. J Exp Med. 1991 May 1;173(5):1053–1063. doi: 10.1084/jem.173.5.1053. [DOI] [PMC free article] [PubMed] [Google Scholar]

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